Preparation of gamma pyrones



pyromeconic acid, is obtained.

United States Patent M 3,171,842 PREPARATION OF GA PYRONES Bryce E.Tate, Niantic, Conn, assignor to Chas. Pfizer & Co., Inc, N ew York, N.Y., a corporation of Delaware No Drawing. Filed June 13, 1962, Ser. No.202,102 Claims. (Cl. 260-3459) The present invention relates to aprocess for the preparation of gamma-pyrones. More particularly it isconcerned With an improved process for the preparation of maltol,3-hydroxy-2-methyl-4-pyrone, a particularly valuable gamma-pyrone, whichis useful, among other things, for its flavor and aroma-enhancingproperties.

While maltol is obtained commercially from wood, for example, bydifficult and expensive extraction processes, it is known to the artthat it can also be obtained by chemical syntheses from othergamma-pyrones. Thus the preparation of maltol from the freely-availableand economical starting material, kojic acid, 2-hydroxymethyl-5-hydroxy-4-pyrone, is disclosed in the pending application of Bryce E.Tate and Robert L. Miller, Serial Number 171,732, filed February 7,1962, now Patent No. 3,130,- 204, and assigned to the assignee of theinstant application.

There is also known to the art another synthesis of maltol which isbased on the disclosure of M. A. Spielman and M. Freifelder in volume69, Journal of the American Chemical Society, pp. 2908-9 (1947). Thissynthesis is carried out in accordance with the following scheme:

pyromeconic acid The instant application is concerned with animprovement in the Spielman et al. process.

In the Spielman et al. article cited, it is disclosed that the yield inthe step (1) in the reaction sequence is 43% and in step (2) the highestyield is reported to be 17%; thus an overall yield of maltol of only7.3% based on It is noteworthy that after many experiments, this lowyield was only obtained after conducting the reduction at a very highpressure (100 atmospheres) and in the presence of an expensive noblemetal catalyst (palladium-on-charcoal).

It has now been found that application of improved processing conditionsrecently disclosed to the art by OBrien et al. in volume 25, Journal ofOrganic Chemistry, p. 86 (1960), to step (1) in the sequence and sub3,171,84 Patented Mar. 2, 19d

Thus, application of the improvements of OBrien et a to increase theyield of Z-di-substituted aminomethylpyr meconic acid followed byapplication of the improv process of the instant invention to themaltol-formatir step allows the yield of maltol to be increased nearfour-fold to a cornercially-feasible level and permits su stantialsavings in process and equipment costs.

It is accordingly a principal object of the present i vention to providean improved means to obtain malt from readily available, economicalgamma-pyrone sta: ing materials.

This and other objects obvious to those skilled in t' art may be readilyachieved by application of the i1 proved process of the presentinvention which compris preparing maltol by treating aZ-di-substituted-amin methylpyromeconic acid with a metal-acid reducingage combination.

By the term 2-disubstituted-aminomethylpyromecor as employed herein andin the appended claims it is be understood that the present inventioncontemplat reaction products derived by treatment of pyromecor acid withformaldehyde and a secondary amine and 1mm to those skilled in the artas Mannich bases. In adt tion to the 2-piperidinomethylpyromeconic aciddisclos by Spielman et al., a number of other Mannich bas may be used.Z-dimethylaminomethylpyromeconic ac: Z-di-n-butylamino-pyromeconic acidand 2-morpholin methylpyromeconic acid are examples of Z-di-su'ostituteaminomethylpyromeconic acids which are especially u: ful.

With respect to the term metal-acid reducing agent e01 binations asemployed herein and in the appended chain it is meant, as is obvious tothose skilled in the art, co] binations of acids with metalsappropriately located the electromotive series of the elements, whichcombir tions provide a reducing action on organic compount As will bediscussed in connection with the process, a. as will be exemplified indetail hereinafter, the ter metal-acid reducing agent combinationscontemplated metals, for example, zinc, iron, aluminum, tin, magne um,and the like, and as acids, strong mineral acids su as, for example,hydrochloric acid and sulfuric acid, a monocarboxylic saturatedopen-chain aliphatic acids tl have from 1 to 10 carbon atoms and whichare soluble the reaction system, such acid being represented by, texample, formic acid, acetic acid, isodecanoic acid, a the like.

The 2 di-substituted-arninomethylpyromeconic aci may be convenientlyprepared by reaction of pyron conic acid with a mixture offormaldehydeand an orgar amine such as, for example, dimethylamine,di-n-but amine, piperidine, morpholine, and the like. Pyrorr conic acidmay be obtained as is described in the Sa copending application, forexample, by decarboxylati of comenic acid Which is in turn obtained byoxidation commercially-available kojic acid. The reaction C0111 tionssuitable for formation of the Mannich base deriy from piperidine aredescribed in the aforementiom Spielman et al. article. However, as hasbeen mention hereinbefore, since higher yields are obtained, it is p1ferred to employ the process of OBrien et al. substituti instead anequivalent amount of pyromeconic acid 1 the kojic acid employed therein.As will be exemplifi :s of water and other solvents such as loweralkanols,

tic acid, and the like; the mixture is treated with an aunt of metalsuch as, for example, zinc, iron, alumin, tin, magnesium, and the like,equivalent to from 111: 1.2 to about 2.5 gram atoms of metal per mole ofnnich base; the resulting suspension is treated with the 1 member of thereducing agent combination .and 1:he ction mixture is maintained at atemperaturepf fr m ut to about 125 ;C.,.preferably, to minimize sidections, from-about .25 toabout 75 ,C.,,and especially Eerably at about5565 C., until paper chromatophic assay indicates .the2-di-substitutedaminomethylomeconic .acid to have been substantiallycompletely :s-umed. Maltol canbeisolated from-the-reaction mixa byadjusting thepI-I to from about ,1 tOgfilbOllt 3 and racting ,theacidicsolution with about 5 volumes of organic solvent such as, for example,chloroform, er, benzene, and the like. Concentration of the oric layercauses crystallinemaltol to precipitate. This be removed byfiltration.

The metal to be employed .i-ntheimproved processrof present inventionmust'be appropriately located in electromotive series to react with theacid ,-1 nember ention may be any strong mineral acid or mono- Iboxylicsaturated open-chain aliphatic acids of from a about .10 carbonatoms soluble inthe, reaction mem and capable of: reactingwith the metaland .providthe conditions required forthe reduction. Whilethe ctmechanism of the reduction, is not clearlyunder- )d, the interactionofmetal ..with acid m ay furnish :trons needed for thereduction oralternatively, the ibination of metal and acid may.furnish an :active 110f hydrogenwhich maybeinvolved in the reducl. Among the ,mineral acidswhich are particularly ctive .are vhydrochloric,and sulfuric and amongfthe anic acids which .are particularly efiective are formic acetic.It-is especially preferred to useeitherihydfouric acid or acetic acid inthisvreaction'since the ltol formed has a tendency to be...ob tai .nedinhigher d and inhigher purity. )f course, the instant invention is alsoto be ,under- 2d,.to contemplate reduction of2-di-substit-uted-aminohylpy-romeconic. acids directly in. solutions inwhich V are prepared. by treatment of pyromeconic acid with naldehyde;and an. amine. TIlnis the,metaliruly'v be ed to the-reaction mixture,thenthe. acid isfadded, and reduction is carried out as describedhereinbeforeand :xemplifiedhereinafter. V The following examples areillustrativeof the process his invention. Example I 1 mixture ofmorpholine, 35 g., 37% aqueous formal- .yde, 32.0 g., and ethanol, 400ml., is allowed to stand 15 minutes, then is stirred vigorously whilepyromeic acid, 33.6 g., is added during '5 minutes. Stirring :ontinuedfor an additional ,16'hours and then the 4 reaction mixture is cooled inan ice bath and the product is collected by filtration. There isobtained an 84% yield of Z-morpholinomethylpyromeconic acid, M.P. 150151C. An additional 8% yield of equally pure product is obtainedafterlconcentration of the filtrate to about onefourth volume, coolingto 5 C. and collecting the crystals by filtration. The total yield ofmaterial is 92% of theory.

To a stirred suspension of 21.1 g. ofthe 2-morpholinomethylpyromeconicacid, zinc dust, 13 g., and Water, 180.

ml., is added 56 ml. of cone. hydrochloric acid at such a rate that thetemperature is maintained between 60 and C.; about 15 minutes arerequired. The mixture is 7 then stirred for an additional 1.5 hours at65 C.; during this time the reaction temperature is maintained byapplication ofan external heating bath as necessary. The suspension isthen heated to 90 C. and is filtered while hot to remove unreacted zincmetal. cooled to 30 C. and is adjusted to pH 2 by the addition of 50%aqueous sodium hydroxide solution. The solution is extracted withone-fifth volume of chloroform 6 times and the chloroform layer isconcentrated to one- .fourth volume and cooled. Crystalline maltol whichprecipitates is removed by filtration and weighs 4.44 g., 35% yield,l60.l6l C. Concentration of the filtrate to one-third volume yields ,anadditional 2.23 g., 17.7% yield of maltol, M.P. l59 16l C. Atotal yieldof 53% is obtained.

The procedure is repeated substituting for the morpholine,stoichiometrically equivalent amounts of the following bases:piperidine, dimethylamine and di-n-butylamine. Substantially'thesameresults are obtained.

Example I] p The procedure of Example I is repeated substituting for thezinc dust, stoichiometrically equivalent amounts of the .followingmetals: iron, aluminum, tin and magnesium. Substantially the sameresults are'obtained.

Example 111 Arnixture of morpholine, '35 g., -37% aqueousformaldehyde,32.0 g., and ethanol,3400 ml., is allowed to .stand for 15 minutes, thenis stirred vigorously while pyromeconic acid, 33.6 g., is added during 5minutes; the mixture is stirred for an additional .16' hours. To thisstirred suspension of Z-morpholinomethylpyromeconic .acid is; added 0.6gram atoms of zinc metal dust, 500 m1. of waterand then 150 ml. ofconcentrated hydrochloric j acid is added at such a rate thatthentemperature is maintained between 60 and 65 (3.; about 15 minutesare required. The mixture is, then stirred for an additional, 1.5hoursat 65 C.; during thistime the reaction temperature is maintainedby' external heating. The suspension is then heated to C. andis filteredwhile hot to remove unreacted zincmetal. The filtrateis cooled to 30 C.,is

adjusted to-pH 2 by the addition 'of 50% aqueous sodium hydroxidesolution and the maltol isextracted by the procedure of Example I.Substantially the same results are obtained. 1

The procedure of Example IV'is illustrative of that,

,embodiment of the instant invention wherein the improved process isapplied to the reaction mixture in which the Mannich base is prepared.

The filtrate is the improvement which comprises treating the said2-disubstituted-aminomethylpyromeconic acid Mannich base under reducingconditions with a metal-acid reducing agent combination.

2. A process as in claim 1 wherein the saidZ-di-substituted-aminomethylpyromeconic acid Mannich base is 2-morpholinomethylpyromeconic acid Mannich base.

8. A process as in claim 1 wherein the said2-di-substituted-arninomethylpyromeconic acid Mannich base is 2-piperidinomethylpyromeconic acid Mannich base.

4. A process as in claim 1 wherein the said metal agent is Zinc and thesaid acid agent is hydrochloric acid.

5. A process as in claim 1 wherein the said metal age is zinc and thesaid acid agent is acetic acid.

References Cited in the file of this patent 5 Spielman et al.: JournalAmerican Chemical Socie vol. 69, pp. 2908-2909 (1947).

OBrien et al.: Journal Organic Chemistry, vol. 2 pp. 86-89 (1960).

Campbell et al.: Journal Organic Chemistry, vol. I 10 pp. 221-226(1950).

Fieser et al.: Advanced Organic Chemistry, page 11 Reinhold PublishingCorp., New York (1961).

1. IN A PROCESS FOR THE REDUCTION OF 2-DI-SUBSTITUTEDAMINOMETHYLPYROMECONIC ACID MANNICH BASES TO MALTOL, THE IMPROVEMENT WHICHCOMPRISES TREATING THE SAID 2-DISUBSTITUTED-AMINOMETHYLPYROMECONIC ACIDMANNICH BASE UNDER REDUCING CONDITIONS WITH A METAL-ACID REDUCING AGENTCOMBINATION.